Multifaceted Roles of TRIM38 in Innate Immune and Inflammatory Responses

REVIEW

Multifaceted roles of TRIM38 in innate immune and inﬂammatory responses

Ming-Ming Hu and Hong-Bing Shu

The tripartite motif-containing (TRIM) proteins represent the largest E3 ubiquitin ligase family. The multifaceted roles of TRIM38 in innate immunity and inflammation have been intensively investigated in recent years. TRIM38 is essential for cytosolic RNA or DNA sensor-mediated innate immune responses to both RNA and DNA viruses, while negatively regulating TLR3/4- and TNF/IL-1β-triggered inflammatory responses. In these processes, TRIM38 acts as an E3 ubiquitin or SUMO ligase, which targets key cellular signaling components, or as an enzymatic activity-independent regulator. This review summarizes recent advances that highlight the critical roles of TRIM38 in the regulation of proper innate immune and inflammatory responses. Cellular & Molecular Immunology (2017) 14, 331–338; doi:10.1038/cmi.2016.66; published online 13 February 2017

Keywords: Inﬂammation; Innate Immunity; Signaling transduction; TRIM38; Type I Interferon

INTRODUCTION Various mechanisms regulate innate immune and inflam- The innate immune system is the first line of host defense matory responses. In the past years, increasing evidence against infection of microbial pathogens. Host cells express suggests that members of the tripartite motif (TRIM) family, several types of germline-encoded pattern-recognition recep- which is the largest family of RING domain-containing E3 tors (PRRs), which sense a wide range of pathogenic compo- ligases, have critical regulatory roles in innate immunity and nents that are named pathogen-associated molecular patterns inflammation.10,11 Although most TRIM family members are (PAMPs), including nucleic acids, lipids, proteins and so on.1 E3 ubiquitin ligases, some members of the TRIM family have According to their subcellular locations and structures, PRRs been suggested to confer E3 ligase activity for ubiquitin-like can be grouped in several families, including plasma or modifiers (UbLs), such as SUMO, NEDD8 and ISG15.12–17 endosomal membrane-bound Toll-like receptors (TLRs), cyto- Among the TRIM family members, TRIM38 has been demon- solic RIG-I-like receptors (RLRs), cytosolic DNA sensors and strated to have important regulatory roles through distinct – cytosolic NOD-like receptors (NLRs).2 5 The membrane- mechanisms in various innate immune and inflammatory bound TLRs are mainly expressed in immune cells, while pathways, which are the focus of this review. RLRs and DNA sensors recognize RNA or DNA in a variety of cell types, including both immune and non-immune cells.6 The STRUCTURE OF TRIM38 NLR family contains more than 20 members. Several members The TRIM proteins derive their names from their common of this family form inflammasomes and trigger inflammatory N-terminal tripartite RBCC motif, which consists of a RING responses, including the secretion of interleukin (IL)-1β via the domain, one or two BBox domains and a coiled-coil domain activation of caspase-1, in response to various pathogenic (CCD).11 The BBox exhibits zinc-finger structure that is highly stimulations.7,8 The signaling through TLRs, RLRs, DNA similar to the RING domain.18,19 Because of the high similarity sensors and NLRs culminates in the expression of downstream of BBox to RING domain, it has been suggested that BBox host defense genes, such as type I interferons (IFNs) and offers an E2 binding site similar to RING and thereby confers inflammatory cytokines, to inhibit replication of pathogens, E3 ligase activity to some TRIM proteins lacking a RING clear pathogen-infected cells, and facilitate adaptive immune domain. For example, a recent work has demonstrated that response.9 TRIM16, a TRIM protein lacking a RING domain, confers E3

Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan 430071, China Correspondence: Dr H-B Shu, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Luo Jia Shan, Wuhan 430071, China. E-mail: [email protected] Received: 19 September 2016; Revised: 10 November 2016; Accepted: 10 November 2016 Multifaceted roles of TRIM38 M-M Hu and H-B Shu

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ubiquitin ligase activity in vitro.20 The CCD is necessary and be induced by various stimuli, such as TLR ligands, type I IFNs, sufficient for oligomerization of TRIM proteins.21–23 In addi- and viral infection, suggesting that TRIM38 is a potential tion, systematic studies have demonstrated that TRIM hetero- interferon-stimulating gene (ISG).28–30 oligomers are formed at least in vitro, which increases the spectrum of their biological functions.20,24 The C-terminal NEGATIVE REGULATION OF TRIM38 ON TLR-MEDIATED domains found in TRIM proteins are quite diverse. The most SIGNALING PATHWAYS universal C-terminal domain is PRY-SPRY (B30.2), which TLRs recognize a set of pathogenic components and have is present in most TRIM proteins, including TRIM38. The critical roles in host defenses against certain microbes. So far, reported functions of the PRY-SPRY domain are divergent. 10 TLRs have been reported in humans (TLR1–10), while Predominantly, this domain mediates protein-protein inter- there are 12 known TLRs in mice (TLR1-9 and TLR11–13).2,32 actions,25 which entails the binding of ubiquitination substrates TLRs contain an extracellular domain to which ligands bind, and determining E3 ligase specificity. In addition, the PRY- a transmembrane domain, and a conserved cytoplasmic SPRY domain is critical for the direct antiviral restriction Toll/IL-1R (TIR) domain, which acts as a platform for the activity of certain TRIM proteins such as TRIM5.26 TRIM38 is recruitment of downstream TIR domain-containing adapter a typical TRIM protein and contains a RING, two BBoxes, proteins and other signaling components upon ligand a CCD and a PRY-SPRY domain.27 It has been shown that stimulation.2 Among the TLRs, TLR3 recognizes viral dsRNA, amino acids C16 and C31 in the RING are critical for the as well as its synthetic analog polyinosinic-polycytidylic acid optimal catalytic activity of TRIM38, and mutation of either of [poly(I:C)] in the endosomes.33 Upon activation, TLR3 recruits these cysteines severely impairs TRIM38-mediated polyubiqui- a co-receptor MEX3B, an accessory protein WDFY1, and the tination of its substrates.28–31 critical adapter TIR domain-containing adapter TRIF (also called TICAM-1).2,34,35 TRIF, in turn, recruits TRAF2/6 and INDUCIBLE EXPRESSION OF TRIM38 two kinase complexes: the IKK complex to activate NF-κBand TRIM38 is ubiquitously expressed in different cell types, such the TBK1 complex to activate IRF3, leading to subsequent as various human and murine cell lines (HEK293, HeLa, induction of proinflammatory cytokines, such as TNF and HCT116, A549, THP-1, and RAW264.7), mouse lung fibro- IL-1β, type I IFNs and ISGs.1 Most other TLRs trigger signaling blasts (MLFs), bone marrow-derived macrophages (BMDMs) through the MyD88-TRAF6-IKK axis to activate NF-κBbut and dendritic cells (BMDCs).27–31 Expression of TRIM38 can not IRF3.1 TLR4, which recognizes lipopolysaccharides (LPS)

Figure 1 TRIM38-mediated negative regulation of TLR3/4-mediated and TNF/IL-1-triggered signaling. After the activation of TLR3/4, TRIM38 is recruited to the adapter protein TRIF, leading to its K48-linked polyubiquitination and degradation, therefore negatively regulating TLR3/4-mediated induction of proinﬂammatory cytokines and type I IFNs. In the early phase of infection, type I IFNs induce the expression of TRIM38, which in turn mediates the degradation of TAB2/3 by a lysosomal pathway, leading to negative regulation of TNF- and IL-1-triggered signaling and inﬂammatory response.

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333 of gram-negative bacteria, is the only receptor that signals TANK-TBK1-NAP1 complex and the transcriptional factor through MyD88-dependent pathways to activate NF-κBand IRF3.49,50 A recent study has indicated that MSX1 is critical for TRIF-dependent pathways to activate both NF-κB and IRF3.36 optimal assembly of the TANK-TBK1-NAP1 complex.51 In mouse RAW264.7 cells, it has been demonstrated that Furthermore, in this process, GSK3β is recruited to TBK1 Trim38 (referred to as the mouse ortholog of human TRIM38) and promotes the self-association and trans-phosphorylation of negatively regulates TLR3/4-mediated NF-κB activation by TBK1, followed by TBK1-mediated phosphorylation of IRF3, targeting TRAF6 for proteasomal degradation.30 Furthermore, leading to the dimerization and translocation of IRF3 to the Trim38 also targets NAP1 for proteasomal degradation, nucleus.52 VISA also recruits TRAF2/6 and the IKK complex, which leads to negative regulation of TLR3/4-mediated IRF3 which then phosphorylate IκBα and activate the transcriptional activation and type I IFN induction.29 An independent study factor NF-κB, leading to translocation of NF-κB to the nucleus. demonstrates that TRIM38 negatively regulates TLR3-mediated The translocated IRF3 and NF-κB cooperatively drive the activation of IRF3 and induction of type I IFNs by mediating transcription of type I IFN genes.53,54 In the late phase of viral proteasomal degradation of TRIF in human cell lines,31 which infection, RIG-I and MDA5 as well as VISA are regulated by represents a distinct mechanism from the previous report. K48-linked polyubiquitination and degradation to avoid their Mouse gene knockout studies suggest that Trim38-deficiency sustained activation.55–61 potentiates poly(I:C)- and LPS-induced, but not R848 (a ligand In addition to polyubiquitination and phosphorylation, for TLR7)- or PGN (a ligand for TLR2)-induced expression sumoylation of RIG-I and MDA5 has also been reported.62,63 of type I IFNs and proinflammatory cytokines in BMDMs, Our recent study suggests that TRIM38 is associated with BMDCs and MLFs.28 Trim38-deficiency also increases the MDA5 and RIG-I and positively regulates MDA5- and RIG-I- serum cytokine levels induced by poly(I:C) and LPS, as well mediated induction of downstream antiviral genes.64 Gene as susceptibility to body weight loss and death triggered by knockout in mice suggests that Trim38 is essential for efficient administration of poly(I:C) or LPS or infection with induction of type I IFNs, proinflammatory cytokines and other S. typhimurium.28 Biochemical experiments indicate that downstream antiviral genes as well as for host defense against Trim38-deficiency abolishes K48-linked polyubiquitination of RNA viruses in vivo.64 Biochemical analysis suggests that Trif and markedly upregulates the protein level of Trif, Trim38 acts as an E3 SUMO1 ligase for Mda5 (referred to as suggesting that Trim38 targets Trif for K48-linked polyubiqui- the mouse ortholog of human MDA5) and Rig-I (referred to as tination and degradation.28 The mechanisms responsible for the mouse ortholog of human RIG-I). Trim38 catalyzes the the negative regulatory roles of TRIM38 on TLR3/4-mediated sumoylation of Mda5 at K43/K865 and Rig-i at K96/K889. In signaling are illustrated in Figure 1. Previously, it has been uninfected cells, K43 of Mda5 is basally sumoylated. Upon viral reported that another E3 ubiquitin ligase, WWP2, also targets infection, the sumoylation at K43 is enhanced, and K865 is TRIF for K48-linked polyubiquitination and proteasomal further sumoylated. Similarly, K889 of Rig-i is basally sumoy- degradation.37 However, WWP2 functions differently with lated in uninfected cells, and K96 is further sumoylated upon TRIM38.WWP2specifically regulates TLR3- but not TLR4- viral infection. Trim38-mediated sumoylations of Mda5 and mediated innate immune and inflammatory responses. Rig-i are important for antagonizing their K48-linked poly- Furthermore, WWP2-deficiency increases TLR3-mediated ubiquitination and degradation in uninfected and early- induction of cytokines in BMDMs but not in BMDCs, whereas infected cells. Previously, it has been demonstrated that depho- Trim38-deficiency increases TLR3/4-mediated induction of sphorylation of Mda5 at S88 and Rig-I at S8/T177 by the cytokines in both cell types. It is possible that Trim38 and phosphatase PP1 following viral infection is critical for their WWP2 function in different cell types and distinct pathways. activation.41 Mutagenesis suggests that sumoylation of Mda5 at K43 and Rig-i at K96 is essential for their dephosphorylation POSITIVE REGULATION OF RLR-MEDIATED INNATE and activation following viral infection.64 These studies provide IMMUNE RESPONSE BY TRIM38 solid evidence that sumoylation of Mda5 and Rig-i is essential RLRs, including RIG-I and MDA5, contain two N-terminal for the efficient onset of innate immune response to RNA tandem CARD domains, an RNA helicase domain and a viruses. In addition, these findings suggest that Mda5 and Rig-i C-terminal domain (CTD), and recognize RNAs of different are regulated by Trim38-mediated sumoylation with similar RNA viruses.38 In the absence of viral infection, RIG-I and mechanisms. Interestingly, it is reported that prolonged EV71 MDA5 are phosphorylated in their respective CARDs to infection causes degradation of TRIM38 in human cells, – suppress their activation in resting cells.39 41 After recognition implying that inactivation of TRIM38 following viral infection of cytosolic viral RNA, RIG-I and MDA5 undergo conforma- is an important immune evasion strategy of RNA viruses.65 tional changes and recruit PP1 for their dephosphorylation,41 leading to their further recruitment of several E3 ubiquitin POSITIVE REGULATION OF THE CGAS-MITA/STING ligases, including TRIM25, RNF135 and TRIM4 for K63-linked PATHWAYS BY TRIM38 polyubiquitination,42–44 followed by their translocation to the Cytosolic DNA derived from viruses, bacteria and the damaged outer membrane of mitochondria, where they activate the host cells induces innate immune responses.66 Although several central adapter VISA (MAVS, CARDIF and IPS-1).45–48 VISA, DNA sensors have been reported to recognize various DNAs together with WDR5 and TRIM14, in turn recruits TRAF3, the in different cell types, it is widely believed that the cyclic

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GMP-AMP (cGAMP) synthase (cGAS) is the major sensor of removed by CCP5/6, leading to the activation of cGAS.87 AKT1 cytosolic DNA in divergent cell types.67–76 phosphorylates cGAS at K305, which inhibits DNA binding to After binding of cytosolic viral or cellular DNA, cGAS cGAS and avoids its sustained activation.89 MITA/STING is undergoes oligomerization and utilizes ATP and GTP for the also regulated by phosphorylation. ULK1 phosphorylates MITA/ synthesis of cyclic GMP–AMP (cGAMP), which then acts as a STING at S366 upon DNA or cGAMP stimulation, leading to second messenger to bind to and activate the central adapter attenuated IRF3 activation.85 TBK1 has been shown to phos- protein MITA (also called STING).77–80 MITA/STING is phorylate MITA/STING at the same residue but positively translocated from the ER to ER-Golgi intermediate compart- regulates MITA/STING-mediated signaling.90 In addition to ments (ERGIC) and the Golgi apparatus.81 In this process, it phosphorylation, MITA/STING is also modified by various types has been shown that the ER-associated protein ZDHHC1 of polyubiquitin chains, which distinctly regulate the activity of facilitates the oligomerization and optimal activation of MITA/ MITA/STING. TRIM56 and TRIM32 catalyze K63-linked poly- STING.82 In addition, another ER-associated protein, called ubiquitination of MITA/STING, leading to its activation.91,92 iRhom2, facilitates translocation and stability of MITA/ AFMR catalyzes K27-linked polyubiquitination of MITA/STING, STING.83 At ERGIC/Golgi apparatus, the kinases TBK1 and which forms a platform for TBK1 recruitment.93 RNF5 catalyzes IKK are recruited to the MITA/STING-associated complex in K48-linked polyubiquitination of MITA/STING, causing the which they phosphorylate IRF3 and IκBα, respectively, leading proteasomal degradation of MITA/STING.94 RNF26 catalyzes to the induction of downstream antiviral genes.84 In the late K11-linked polyubiquitination of MITA/STING, which unlocks phase of viral infection, MITA/STING is further translocated its K48-linked polyubiquitination and prevents its proteasomal to perinuclear microsomes, in which it is degraded via a degradation. RNF26 also appears to negatively regulate innate lysosome-dependent pathway.81,85 immune signaling in a temporal fashion.95 Post-translational modifications, including phosphorylation, Recently, it has been demonstrated that TRIM38 is a SUMO polyubiquitination and glutamylation, have important roles in ligase for both cGAS and MITA/STING.96 Sumoylation of cGAS regulating the cGAS-MITA/STING pathways.9,86–88 For exam- and STING kinetically regulates the innate immune response to ple, TTLL4/6 catalyzes the glutamylation of cGAS, which DNA viral infection (Figure 2). In uninfected cells, Trim38 impairs its DNA-binding and synthase activity in resting cells. catalyzes sumoylation of cGas at K217, which antagonizes its Upon viral infection, the glutamylation modification of cGAS is K48-linked polyubiquitination at K271 and degradation by the

Figure 2 Sumoylation promotes the stability of cGas and Sting and regulates the kinetics of the response to a DNA virus. In uninfected or early-infected cells, cGas and Sting are sumoylated, which promotes their stability and activation by inhibiting K48-linked polyubiquitin- proteasomal and chaperone-mediated degradation (CMA) pathways, respectively, thus promoting an efﬁcient innate immune response to a DNA virus. In the late phase of viral infection, Senp2 mediates the desumoylation of cGas and Sting, leading to their degradation by the proteasomal pathway and CMA, respectively, therefore turning off the innate immune response.

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335 ubiquitin-proteasomal pathway. Upon viral infection, Trim38 USP4 mediate deubiquitination of RIP1, TRAF2 and TAK1, further catalyzes the sumoylation of cGas at K464, which prevents respectively.108,110,111 IthasalsobeenshownthatDUSP14 it from K48-linked polyubiquitination at the same residue and catalyzes dephosphorylation of TAK1, leading to suppression of degradation by the ubiquitin-proteasomal pathway. These pro- TNF and IL-1β-triggered signaling.112 It is possible that different cesses ensure the proper level of cGas and its activation in the enzymes target distinct signaling components in various cell types early phase of viral infection. The activated cGas catalyzes the following TNF or IL-1β stimulation. synthesis of cGAMP, which binds to and activates the ER- Recently, it has been shown that TRIM38 negatively regulates associated Mita/Sting. In the early phase of viral infection, Trim38 TNF- and IL-1β-triggered activation of NF-κBandMAPKsaswell also targets Mita/Sting for sumoylation at K337, which promotes as inflammatory responses.27 TRIM38 promotes the degradation its CTT-mediated oligomerization and prevents its degradation by of TAB2/3 through a lysosomal-dependent pathway, which the CMA pathway. These actions result in optimal activation of requires its C-terminal PRY-SPRY but not the RING domain.27 Mita/Sting as well as induction of downstream antiviral genes. In The degradation of TAB2/3 inhibits recruitment of TAK1 to the late phase of infection, cGas and Mita/Sting are desumoylated upstream adapters RIP1 and TRAF6, leading to inhibition of NF- by SENP2, leading to their K48-linked polyubiquitination-protea- κB and MAPKs and the expression of inflammatory cytokines.27 somal and CMA degradation, respectively. Therefore, the tem- TRIM38 is highly induced by type I IFNs and negatively regulates poral sumoylation of cGas/Mita/Sting by Trim38 and their TNF/IL-1β signaling in IFN-β-primed but not unprimed mouse desumoylation by Senp2 provide important regulatory mechan- immune cells.28 These findings suggest that TRIM38 probably has isms for efficient innate antiviral response at the early phase of important negative regulatory roles in the late phase of inflam- infection and its timely termination at the late phase of infection. matory response to various pathogenic stimuli, which trigger inductionoftypeIIFNsattheearly phase of infection (Figure 1). REGULATION OF THE TNF/IL-1b-TRIGGERED INFLAMMATORY RESPONSE BY TRIM38 TRIM38 IN AUTOIMMUNE DISEASES The proinflammatory cytokines TNF and IL-1β have central Several TRIM family proteins have been reported to be roles in many diseases, such as inflammation, autoimmunity associated with certain autoimmune diseases.113,114 A recent and cancers. After the binding of TNF to TNF receptor 1 study clearly demonstrates that TRIM38 is a valid target for (TNFR1), the receptor recruits TRADD, TRAF2/5, cIAP1/2 and auto-antibodies in primary Sjögren's syndrome (SS).115 RIP1 to form a large receptor-associated complex, in which In primary SS, the presence of anti-TRIM21 has been RIP1 undergoes K63-linked polyubiquitination. The TAK1- associated with increased disease severity.116 It has also been associated chaperones TAB2 and TAB3 bind to K63-linked shown that anti-TRIM38 positivity is significantly associated polyubiquitin chains of RIP1, which in turn activates down- with the presence of auto-antibodies to TRIM21. However, stream kinases, leading to the activation of transcription factors how TRIM38 is involved in autoimmune diseases is still NF-κB and AP1.97,98 unknown. It has been shown that mouse TRIM21-reactive IL-1β binds to IL-1 receptor (IL-1R), leading to recruitment antibodies penetrate live salivary gland cells in a mouse of the IL-1R accessory protein (IL-1RAcP) and the adapter model.117 It is possible that anti-TRIM38 penetrates live cells, protein MyD88. MyD88 further recruits IRAK1/4 and TRAF6 causing dysregulated inflammatory responses. to the receptor complex, in which TRAF6 catalyzes K63-linked Several studies suggest that constitutive activation of MDA5 and autoubiquitination and/or the synthesis of unanchored K63- RIG-I derived from viral infection or their genetic mutations is linked polyubiquitin chains. These polyubiquitin chains recruit associated with three different types of autoimmune diseases the TAK1-TAB1-TAB2/3 complex, causing TAK1 autopho- including Aicardi-Goutières syndrome, systemic lupus erythema- sphorylation and activation. TAK1 ultimately activates NF-κB tosus and Singleton–Merten syndrome.118–122 Deregulation of and MAPKs, leading to the induction of various proinflamma- the cGAS-MITA/STING pathway also causes lethal autoimmune tory cytokines and chemokines.97,99 diseases such as Aicardi-Goutières Syndrome and STING- TNF- and IL-1β-triggered signaling is timely downregulated or associated vasculopathy with onset in infancy (SAVI). Considering terminated to avoid excessive inflammatory responses in host the important roles of TRIM38-mediated sumoylation in the cells. Several proteins have been reported to terminate TNF and regulation of the activation and stability of MDA5, RIG-I, cGAS IL-1β signaling by targeting various signaling components in the and MITA/STING, this enzyme may serve as a potential target for pathways. For example, MARCH8, cIAP1/2 and RBCK1 have drug development for autoimmune diseases. been shown to induce K48-linked polyubiquitination and proteasome-dependent degradation of ILRAcP, RIP1 and TAB2/3, CONCLUDING REMARKS respectively.100–102 TRIM5α interacts with the TAK1-TAB1- Recent studies have demonstrated multifaceted roles of TRIM38 TAB2/3 complex and promotes TAB2 degradation via a in innate immune and inflammatory responses. TRIM38 acts lysosome-dependent approach.103 Several deubiquitinating as a SUMO ligase and targets RIG-I/MDA5 and cGAS/STING enzymes have also been shown to have negative regulatory roles for SUMO1 modification, which is essential for their optimal in TNF and IL-1β signaling. A20, USP2a, USP4 and USP20 activation and stability. Therefore, TRIM38 is essential for mediate deubiquitination of TRAF6,104–107 whereas CYLD deu- efficient innate immune responses to both RNA and DNA biquitinates TRAF6 and IKKγ.108,109 Inaddition,A20,CYLD,and viruses. In these responses, TRIM38 functions with similar

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biochemical mechanisms, in that sumoylation of the RNA and 9 Shu HB, Wang YY. Adding to the STING. Immunity 2014; 41: – DNA sensors by TRIM38 prevents their degradation. TRIM38 871 873. 10 Ozato K, Shin DM, Chang TH, Morse HC 3rd. TRIM family proteins can also act as a ubiquitin ligase that targets TRIF for K48-linked and their emerging roles in innate immunity. Nat Rev Immunol 2008; polyubiquitination and degradation and therefore negatively 8:849–860. 11 Versteeg GA, Benke S, Garcia-Sastre A, Rajsbaum R. InTRIMsic regulates TLR3/4-mediated innate immune responses. In addi- immunity: positive and negative regulation of immune signaling by tion, TRIM38 can mediate lysosomal degradation of TAB2/3 in tripartite motif proteins. Cytokine Growth Factor Rev 2014; 25: an enzymatic activity-independent manner to negatively regulate 563–576. β fl 12 Amir RE, Iwai K, Ciechanover A. The NEDD8 pathway is essential for TNF/IL-1 -triggered in ammatory responses. 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